Novel fusion protein PK5-RL-Gal-3C inhibits hepatocellular carcinoma via anti-angiogenesis and cytotoxicity.

BACKGROUND: Galectin-3 (Gal-3), the only chimeric ß-galactosides-binding lectin, consists of Gal-3N (N-terminal regulatory peptide) and Gal-3C (C-terminal carbohydrate-recognition domain). Interestingly, Gal-3C could specifically inhibit endogenous full-length Gal-3 to exhibit anti-tumor activity. Here, we aimed to further improve the anti-tumor activity of Gal-3C via developing novel fusion proteins. METHODS: PK5 (the fifth kringle domain of plasminogen) was introduced to the N-terminus of Gal-3C via rigid linker (RL) to generate novel fusion protein PK5-RL-Gal-3C. Then, we investigated the anti-tumor activity of PK5-RL-Gal-3C in vivo and in vitro by using several experiments, and figured out their molecular mechanisms in anti-angiogenesis and cytotoxicity to hepatocellular carcinoma (HCC). RESULTS: Our results show that PK5-RL-Gal-3C can inhibit HCC both in vivo and in vitro without obvious toxicity, and also significantly prolong the survival time of tumor-bearing mice. Mechanically, we find that PK5-RL-Gal-3C inhibits angiogenesis and show cytotoxicity to HCC. In detail, HUVEC-related and matrigel plug assays indicate that PK5-RL-Gal-3C plays an important role in inhibiting angiogenesis by regulating HIF1α/VEGF and Ang-2 both in vivo and in vitro. Moreover, PK5-RL-Gal-3C induces cell cycle arrest at G1 phase and apoptosis with inhibition of Cyclin D1, Cyclin D3, CDK4, and Bcl-2, but activation of p27, p21, caspase-3, -8 and -9. CONCLUSION: Novel fusion protein PK5-RL-Gal-3C is potent therapeutic agent by inhibiting tumor angiogenesis in HCC and potential antagonist of Gal-3, which provides new strategy for exploring novel antagonist of Gal-3 and promotes their application in clinical treatment.

CD36 regulates LPS-induced acute lung injury by promoting macrophages M1 polarization.

M1 polarization of macrophages works as a promoter in pathogenesis of acute lung injury / acute respiratory distress syndrome (ALI/ARDS) by the secretion of pro-inflammatory cytokines and recruiting other inflammatory cells. Lipopolysaccharide (LPS), a critical component of the wall of gram-negative bacteria, can induce M1 polarization and ALI. Recently, cluster of differentiation 36 (CD36) has been reported to be associated with inflammatory responses. However, it has not yet been clarified whether CD36 in macrophages is involved in LPS-induced ALI. Herein, we demonstrated that in macrophages, LPS-induced ALI was regulated by CD36. Loss of CD36 attenuated LPS-induced ALI by reducing M1 polarization. Mechanistically, CD36 promoted macrophage M1 polarization by regulating CD14 associated with TLR4 during LPS stimulation. The findings of this study, clarified the mechanism of LPS-induced ALI through CD36 in macrophages, which provides a potential target for the prevention and treatment of ALI.

Inhibition of Stearoyl-CoA Desaturase 1 Potentiates Anti-tumor Activity of Amodiaquine in Non-small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer related death with few therapeutic treatment options. Under adverse tumor microenvironment, autophagy is an important mechanism of metabolic adaptations to sustain the survival and proliferation of tumor cells. Therefore, targeting autophagic activity represents a promising opportunity for NSCLC treatment. Here, we found that amodiaquine (AQ) increased autophagosome numbers and LC3BII and p62 at protein levels in A549 lung cancer cells suggesting the blockade of autophagic flux by AQ. To identify the key metabolic vulnerability associated with autophagy inhibition by AQ treatment, we then performed transcriptomics analysis in the presence or absence of AQ in A549 lung cancer cells and found stearoyl-CoA desaturase 1 (SCD1) was one of the most highly upregulated with AQ exposure. The induction of SCD1 by AQ exposure at both protein and mRNA level suggests that SCD1 could represent a potential therapeutic target of AQ treatment. Treatment of AQ in combination with SCD1 inhibition by A939572 demonstrated robust synergistic anti-cancer efficacy in cell proliferation assay and a lung cancer mouse xenograft model. Taken together, our study identified SCD1 could be a new therapeutic target upon autophagy inhibition by AQ exposure. Combinational treatment of autophagy inhibition and SCD1 inhibition achieves synergistic anti-tumor effect both in vitro and in vivo. This combinational approach could be a promising strategy for NSCLC treatment.

High-Depth Transcriptome Reveals Differences in Natural Haploid Ginkgo biloba L. Due to the Effect of Reduced Gene Dosage.

As a representative of gymnosperms, the discovery of natural haploids of Ginkgo biloba L. has opened a new door for its research. Haploid germplasm has always been a research material of interest to researchers because of its special characteristics. However, we do not yet know the special features and mechanisms of haploid ginkgo following this significant discovery. In this study, we conducted a homogenous garden experiment on haploid and diploid ginkgo to explore the differences in growth, physiology and biochemistry between the two. Additionally, a high-depth transcriptome database of both was established to reveal their transcriptional differences. The results showed that haploid ginkgo exhibited weaker growth potential, lower photosynthesis and flavonoid accumulation capacity. Although the up-regulated expression of DEGs in haploid ginkgo reached 46.7% of the total DEGs in the whole transcriptome data, the gene sets of photosynthesis metabolic, glycolysis/gluconeogenesis and flavonoid biosynthesis pathways, which were significantly related to these differences, were found to show a significant down-regulated expression trend by gene set enrichment analysis (GSEA). We further found that the major metabolic pathways in the haploid ginkgo transcriptional database were down-regulated in expression compared to the diploid. This study reveals for the first time the phenotypic, growth and physiological differences in haploid ginkgos, and demonstrates their transcriptional patterns based on high-depth transcriptomic data, laying the foundation for subsequent in-depth studies of haploid ginkgos.

Cellular retinol binding protein-1 inhibits cancer stemness via upregulating WIF1 to suppress Wnt/ß-catenin pathway in hepatocellular carcinoma.

BACKGROUND: CRBP-1, a cytosolic chaperone of vitamin A, is identified in a serious number of cancers; however, its biological role in hepatocellular carcinoma (HCC) needs to be further explored. The aim of our present study is to explore the roles and mechanisms of CRBP-1 in regulating liver cancer by using in vitro and in vivo biology approaches. METHODS: The expression level of CRBP-1 was detected using immunohistochemistry in HCC and matching adjacent non-tumorous liver tissues. Following established stable CRBP-1 overexpressed HCC cell lines, the cell growth and tumorigenicity were investigated both in vitro and in vivo. Intracellular retinoic acid was quantified by ELISA. The relationship between CRBP-1 and WIF1 was validated by using dual luciferase and ChIP analyses. RESULTS: The low expression of CRBP-1 was observed in HCC tissues compared to the normal liver tissues, while high CRBP-1 expression correlated with clinicopathological characteristics and increased overall survival in HCC patients. Overexpression of CRBP-1 significantly inhibited cell growth and tumorigenicity both in vitro and in vivo. Moreover, overexpression of CRBP-1 suppressed tumorsphere formation and cancer stemness related genes expression in HCC. Mechanically, CRBP-1 inhibited Wnt/ß-catenin signaling pathway to suppress cancer cell stemness of HCC. Furthermore, our results revealed that CRBP-1 could increase the intracellular levels of retinoic acid, which induced the activation of RARs/RXRs leading to the transcriptional expression of WIF1, a secreted antagonist of the Wnt/ß-catenin signaling pathway, by physically interacting with the region on WIF1 promoter. CONCLUSION: Our findings reveal that CRBP-1 is a crucial player in the initiation and progression of HCC, which provide a novel independent prognostic biomarker and therapeutic target for the diagnosis and treatment of HCC.

Lenvatinib enhances T cell immunity and the efficacy of adoptive chimeric antigen receptor-modified T cells by decreasing myeloid-derived suppressor cells in cancer.

BACKGROUND: Lenvatinib, a tyrosine kinase inhibitor, has been approved for the treatment of several cancers. However, its regulatory activity and related mechanisms on T cell antitumour immunity need to be further investigated. METHODS: The antitumour activity of lenvatinib in immunocompetent and immunodeficient mice was compared to determine the role of T cell immunity. The antitumour activity of T cells was analysed by cytokine production and adoptive T cell therapy. The immunosuppressive effects of MDSCs on T cells were determined by detecting cytokine production in T cells after being cocultured with MDSCs. The adjuvant immunotherapy effect of lenvatinib was determined by combination therapy with CAR-T cells targeted carbonic anhydrase IX (CAIX) in a murine renal cancer model. RESULTS: The antitumour activity of lenvatinib was greater in immunocompetent mice than in immunodeficient mice and was attenuated by CD8+T cell depletion. Lenvatinib increased proliferation, tumour infiltration and antitumour activity of T cells. Importantly, adoptive transfer of lenvatinib-treated T cells showed a long-term antitumour response in vivo. Mechanistically, lenvatinib upregulated T cell-related chemokines (CXCL10 and CCL8) in tumours and decreased the frequency and immunosuppressive activity of MDSCs. Furthermore, lenvatinib enhanced the efficacy of CAR-T cells in a murine renal cancer model. CONCLUSION: Our study revealed novel antitumour mechanisms of lenvatinib by enhancing T cell-mediated antitumour immunity. These findings are of great significance for guiding the clinical use of lenvatinib and provide a good candidate for future combination therapy with T-cell therapies or other immunotherapies.

An oral 2-hydroxypropyl-ß-cyclodextrin-loaded spirooxindole-pyrrolizidine derivative restores p53 activity via targeting MDM2 and JNK1/2 in hepatocellular carcinoma.

Validation of a small molecular compound targeting the oncogenic pathways is the primary approach for the development of the anti-cancer drugs. In the present study, we employed the computational mimic drug targets prediction software to foresee the molecular targets of a series of spirooxindole-pyrrolizidine derivatives, which were synthesized by our laboratory viatargeted combinational chemistry. We found that CPHSP, a novel spirooxindole-pyrrolizidine derivative, can target the MDM2/p53 signaling that is essential for the tumorigenesis of hepatocellular carcinoma (HCC). To validate its anti-tumoral function, we firstly established the soluble receipt of CPHSP through 2-hydroxypropyl-ß-cyclodextrin (HBC) loading and showed that oral administration of HBC-loaded CPHSP significantly inhibited the tumor growth and prolonged the survival time of tumor-bearing mice in the subcutaneously human hepatoma cells-xenografted nude mouse model of HCC. Immunohistochemistry staining showed that HBC-loaded CPHSP treatment suppressed the proliferation and induced apoptosis of tumor cells in this model. Our mechanistic studies showed that CPHSP treatment inhibited MDM2 protein expression and up-regulated p53 activity and activated MKK4/MKK7/JNK1/2/C-Jun signaling pathway, which resulted in cell cycle arrest and apoptosis of HepG2 cells in vitro. Moreover, we showed that JNK1/2 activation could also up-regulate p53 expression in CPHSP-treated HepG2 cells. Finally, we documented the antitumor activities of oral administration of the HBC-loaded CPHSP in the ML-1 bearing orthotopic mouse model. In summary, this study suggests that oral administration of HBC-loaded CPHSP is a safe and effective treatment for HCC, of which the clinical potency for patients with HCC warrants further studies.

Human Babesiosis in China: a systematic review.

Human babesiosis, a worldwide emerging tick-borne disease, is caused by the intraerythrocytic apicomplexan parasite, babesia. In recent years, the number of infected patients globally has continued to rise, and thus human babesiosis poses a significant public health threat. Therefore, stronger initiatives should be undertaken to prevent further spread and development of this disease. In the present review, we summarize the epidemiology of reported human babesiosis cases in China from 1993 until now. The data show that Babesia microti is the dominant species causing human babesiosis in China and has led to more than 100 human infections thus far, where Babesia crassa-like is the second-most common. Moreover, Guangxi province is the second-most infected area after the Heilongjiang province. We also review the babesia life cycle, manifestation, diagnosis, and treatment. Additionally, we discuss babesiosis prevention strategies to raise public awareness, and also provide suggestions for improved babesiosis control.

Cleavage and phosphorylation: important post-translational modifications of galectin-3.

As the unique chimeric member of the ß-galactoside-binding protein family, galectin-3 is a multivalent and multifunctional oncogenic protein involved in multiple physiological and pathological processes, including cell growth, cell differentiation, cell adhesion, RNA splicing, cell apoptosis, and malignant transformation. Post-translational modifications can effectively increase a protein's functional diversity, either by degradation or adding chemical modifications, thus regulating activity, localization, and ligand interaction. In order to clearly understand the functional mechanisms of galectin-3 involved in normal cell biology and pathogenesis, here, we have summarized the previously reported post-translational modifications of galectin-3, including cleavage and phosphorylation. Cleavage of galectin-3 by MMPs, PSA, and proteases from parasites generated intact carbohydrate-recognition domain and N-terminal peptides of varying lengths that retained lectin binding activity but lost multivalence. Serine and tyrosine phosphorylation of galectin-3 by c-Abl, CKI, and GSK-3ß could regulate its localization and associated signal transduction. Accordingly, cleavage and phosphorylation play an important role in regulating galectin-3 function via altering its multivalence, localization, and ligand interaction.

H1/pHGFK1 nanoparticles exert anti-tumoural and radiosensitising effects by inhibition of MET in glioblastoma.

BACKGROUND: The therapeutic resistance to ionising radiation (IR) and anti-angiogenesis mainly impair the prognosis of patients with glioblastoma. The primary and secondary MET aberrant activation is one crucial factor for these resistances. The kringle 1 domain of hepatocyte growth factor (HGFK1), an angiogenic inhibitor, contains a high-affinity binding domain of MET; however, its effects on glioblastoma remain elusive. METHODS: We formed the nanoparticles consisting of a folate receptor-targeted nanoparticle-mediated HGFK1 gene (H1/pHGFK1) and studied its anti-tumoural and radiosensitive activities in both subcutaneous and orthotopic human glioma cell-xenografted mouse models. We then elucidated its molecular mechanisms in human glioblastoma cell lines in vitro. RESULTS: We demonstrated for the first time that peritumoural injection of H1/pHGFK1 nanoparticles significantly inhibited tumour growth and prolonged survival in tumour-bearing mice, as well as enhanced the anti-tumoural efficacies of IR in vivo by reducing Ki-67 expression, enhancing TUNEL staining-indicated apoptotic indexes, reducing microvascular intensity and reversing IR-induced MET overexpression in tumour tissues. Furthermore, we showed that HGFK1 suppressed the proliferation and induced cell apoptosis and enhanced sensitivity to IR in glioblastoma cell lines, mainly by suppressing the activities of MET receptor, down-regulating ATM-Chk2 axis but up-regulating Chk1. CONCLUSIONS: H1/pHGFK1 exerts anti-tumoural and radiosensitive activities mainly through the inhibition and reversal of IR-induced MET and ATM-Chk2 axis activities in glioblastoma. H1/pHGFK1 nanoparticles are a potential radiosensitiser and angiogenic inhibitor for glioblastoma treatment.

Oral administration of indole substituted dipyrido[2,3-d]pyrimidine derivative exhibits anti-tumor activity via inhibiting AKT and ERK1/2 on hepatocellular carcinoma.

Development of an effective and safe anti-cancer drug is an urgent request for hepatocellular carcinoma (HCC). In this study, we synthesized a series of novel indole substituted dihydropyrido[2,3-d]pyrimidines through the multicomponent reactions to connect pyrido[2,3-d]pyrimidine and indole moities via an one-pot three-component reaction of 3-cyanoacetyl indoles 1, various aromatic aldehyde 2, and 2,6-diaminopyrimidin-4(3H)-one 3. Subsequently, we screened their cytotoxicity via CCK-8 assay in HepG2 cells, a human hepatoma cell line and chose compound 4p that showed the lowest dosage of IC50 to study the antitumor activities to HCC. Interestingly, 4p significantly induced the cell cycle arrest and apoptosis of HepG2 via targeting AKT and ERK1/2 signaling pathways in vitro. To improve the solubility of compound 4p, we hosted this compound into the substituted glucopyranose ring of (2-Hydroxypropyl)-ß-cyclodextrin (HBC), a cosolvent approved by FDA with the help of ultrasonication and heating. Finally, we showed that oral administration of HBC-hosted 4p effectively inhibited tumor growth and prolonged the survival time of tumor-bearing mice in subcutaneously xenografted model. These results suggest that multicomponent reactions connecting pyrido[2,3-d]pyrimidine and indole moities is a productive and economical method for the synthesis of anticancer compound, and oral administration of HBC-hosted 4p is an effective and safe agents for treatment of HCC, whose clinical application potency warrant further studies.

Novel applications for an established antimalarial drug: tumoricidal activity of quinacrine.

Quinacrine (QC), a synthetic antimalarial drug, was consistently used worldwide to combat malaria during the last century. Interestingly, later studies revealed that it also displays various additional properties, specifically antitumor activity. QC's antitumor activity occurs via a variety of pathways, including DNA intercalation, angiogenesis inhibition, signal transduction regulation, cell cycle arrest and autophagy induction. In combination with traditional therapies such as chemotherapy and radiotherapy, QC has also displayed synergistic effects against tumors, which may open promising therapeutic avenues. However, the breadth and complexity of its antitumor mechanisms have not yet been fully elucidated. In this review, we have systematically categorized QC's reported antitumor mechanisms from recent studies, to enable a deeper understanding of its antitumor activity.

JNK1/2 and ERK1/2 provides vital clues about tumor recurrence and survival in hepatocellular carcinoma patients.

AIM: To explore JNK1/2 and ERK1/2 activation in hepatocellular carcinoma (HCC) patients. PATIENTS & METHODS: Phosphorylated-JNK1/2 and -ERK1/2 (p-JNK1/2 and p-ERK1/2) expressions were determined and analyzed in 104 unique HCC tissue specimens. RESULTS: Expression of p-JNK1/2 and p-ERK1/2 was not correlated with clinicopathological characteristics. High p-JNK1/2 and low p-ERK1/2 expressions predicated significantly lower tumor recurrence for HCC patients. However, HCC patients with low p-JNK1/2 and high p-ERK1/2 had higher tumor recurrence. Moreover, p-JNK1/2 positively, but p-ERK1/2 negatively, associated with overall survival (OS) and recurrence-free survival (RFS) in HCC patients. In addition, HCC patients with simultaneous low p-JNK1/2 and high p-ERK1/2 had poorer OS and RFS. On the contrary, patients with high p-JNK1/2 and low p-ERK1/2 presented better OS and RFS. CONCLUSION: HCC patients with low p-JNK1/2 and high p-ERK1/2 either independently or simultaneously, had significantly higher tumor recurrence and worse OS.

The inhibitory effects of a rhamnogalacturonan I (RG-I) domain from ginseng pectin on galectin-3 and its structure-activity relationship.

Pectin has been shown to inhibit the actions of galectin-3, a ß-galactoside-binding protein associated with cancer progression. The structural features of pectin involved in this activity remain unclear. We investigated the effects of different ginseng pectins on galectin-3 action. The rhamnogalacturonan I-rich pectin fragment, RG-I-4, potently inhibited galectin-3-mediated hemagglutination, cancer cell adhesion and homotypic aggregation, and binding of galectin-3 to T-cells. RG-I-4 specifically bound to the carbohydrate recognition domain of galectin-3 with a dissociation constant of 22.2 nm, which was determined by surface plasmon resonance analysis. The structure-activity relationship of RG-I-4 was investigated by modifying the structure through various enzymatic and chemical methods followed by activity tests. The results showed that (a) galactan side chains were essential to the activity of RG-I-4, whereas arabinan side chains positively or negatively regulated the activity depending on their location within the RG-I-4 molecule. (b) The activity of galactan chain was proportional to its length up to 4 Gal residues and largely unchanged thereafter. (c) The majority of galactan side chains in RG-I-4 were short with low activities. (d) The high activity of RG-I-4 resulted from the cooperative action of these side chains. (e) The backbone of the molecule was very important to RG-I-4 activity, possibly by maintaining a structural conformation of the whole molecule. (f) The isolated backbone could bind galectin-3, which was insensitive to lactose treatment. The novel discovery that the side chains and backbone play distinct roles in regulating RG-I-4 activity is valuable for producing highly active pectin-based galectin-3 inhibitors.

Reproductive toxicity of cadmium stress in male animals.

Cadmium (Cd) is a common heavy metal pollutant in the environment, and the widespread use of products containing Cd compounds in industry has led to excessive levels in the environment, which enter the animal body through the food chain, thus seriously affecting the reproductive development of animals. Related studies have reported that Cd severely affects spermatogonia development and spermatogenesis in animals. In contrast, the reproductive toxicity of Cd in males and its mechanism of action have not been clarified. Therefore, this paper reviewed the toxic effects of Cd on germ cells, spermatogonia somatic cells and hypothalamic-pituitary-gonadal axis (HPG axis) of male animals and its toxic action mechanisms of oxidative stress, apoptosis and autophagy from the perspectives of cytology, genetics and neuroendocrinology. The effects of Cd stress on epigenetic modification of reproductive development in male animals were also analyzed. We hope to provide a reference for the in-depth study of the toxicity of Cd on male animal reproduction.

Lipid-focused dietary education intervention in pregnant women: study protocol for an open-label, parallel, randomised, intervention study addressing adverse pregnancy outcomes in China.

INTRODUCTION: The incidence of infants who are large-for-gestational-age (LGA) is on the rise in China, and its detrimental effects on health have received increasing attention. Diet-based interventions have the potential to reduce adverse birth outcomes, particularly in decreasing the occurrence of LGA infants. We aim to evaluate the effect of lipid-focused diet education based on the theories of behaviour change in pregnant women on maternal and offspring outcomes through a randomised controlled trial. METHODS AND ANALYSIS: We have designed an open-label, parallel, multicentre randomised controlled trial in collaboration with three hospitals in Beijing, China.Pregnant women will be recruited before reaching 12 weeks of gestation and will be randomised in a 1:1:1 ratio into three arms: (1) online education arm, (2) pregnancy nutrition checklist and 'one-page flyer' arm and (3) routine antenatal education. The primary outcome LGA will be recorded at birth. Demographic information, physical activity, sleep and medical history will be collected through questionnaires and case cards prior to enrolment. Questionnaires will also be used to collect dietary behaviours and psychosocial factors of pregnant women at enrolment, at 24-28 weeks and 34-36 weeks of gestation. Additionally, information on breastfeeding and complementary food supplementation for infants and young children will be obtained through questionnaires. Physical development indicators of children and taste tests will be assessed 3 years after delivery. ETHICS AND DISSEMINATION: The study has received ethical approval from the Capital Medical University Ethics Committee and other collaborating study centres. Informed consent will be introduced to pregnant women, and their consent will be obtained. The findings will be reported in relevant national and international academic conferences and peer-reviewed publications. TRIAL REGISTRATION NUMBER: ChiCTR2300071126.

Immunotherapy and drug sensitivity predictive roles of a novel prognostic model in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most significant causes of cancer-related deaths in the worldwide. Currently, predicting the survival of patients with HCC and developing treatment drugs still remain a significant challenge. In this study, we employed prognosis-related genes to develop and externally validate a predictive risk model. Furthermore, the correlation between signaling pathways, immune cell infiltration, immunotherapy response, drug sensitivity, and risk score was investigated using different algorithm platforms in HCC. Our results showed that 11 differentially expressed genes including UBE2C, PTTG1, TOP2A, SPP1, FCN3, SLC22A1, ADH4, CYP2C8, SLC10A1, F9, and FBP1 were identified as being related to prognosis, which were integrated to construct a prediction model. Our model could accurately predict patients' overall survival using both internal and external datasets. Moreover, a strong correlation was revealed between the signaling pathway, immune cell infiltration, immunotherapy response, and risk score. Importantly, a novel potential drug candidate for HCC treatment was discovered based on the risk score and also validated through ex vivo experiments. Our finds offer a novel perspective on prognosis prediction and drug exploration for cancer patients.

Molecular mechanism of co-stimulatory domains in promoting CAR-T cell anti-tumor efficacy.

Chimeric antigen receptor (CAR)-engineered T cells have been defined as 'living drug'. Adding a co-stimulatory domain (CSD) has enhanced the anti-hematological effects of CAR-T cells, thereby elevating their viability for medicinal applications. Various CSDs have helped prepare CAR-T cells to study anti-tumor efficacy. Previous studies have described and summarized the anti-tumor efficacy of CAR-T cells obtained from different CSDs. However, the underlying molecular mechanisms by which different CSDs affect CAR-T function have been rarely reported. The role of CSDs in T cells has been significantly studied, but whether they can play a unique role as a part of the CAR structure remains undetermined. Here, we summarized the effects of CSDs on CAR-T signaling pathways based on the limited references and speculated the possible mechanism depending on the specific characteristics of CAR-T cells. This review will help understand the molecular mechanism of CSDs in CAR-T cells that exert different anti-tumor effects while providing potential guidance for further interventions to enhance anti-tumor efficacy in immunotherapy.

PA suppresses antitumor immunity of T cells by disturbing mitochondrial activity through Akt/mTOR-mediated Ca2+ flux.

Deciphering the mechanisms behind how T cells become exhausted and regulatory T cells (Tregs) differentiate in a tumor microenvironment (TME) will significantly benefit cancer immunotherapy. A common metabolic alteration feature in TME is lipid accumulation, associated with T cell exhaustion and Treg differentiation. However, the regulatory role of free fatty acids (FFA) on T cell antitumor immunity has yet to be clearly illustrated. Our study observed that palmitic acid (PA), the most abundant saturated FFA in mouse plasma, enhanced T cell exhaustion and Tregs population in TME and increased tumor growth. In contrast, oleic acid (OA), a monounsaturated FFA, rescued PA-induced T cell exhaustion, decreased Treg population, and ameliorated T cell antitumor immunity in an obese mouse model. Mechanistically, mitochondrial metabolic activity is critical in maintaining T cell function, which PA attenuated. PA-induced T cell exhaustion and Treg formation depended on CD36 and Akt/mTOR-mediated calcium signaling. The study described a new mechanism of PA-induced downregulation of antitumor immunity of T cells and the therapeutic potential behind its restoration by targeting PA.